Adolescent binge drinking permanently alters adult brain sensitivity to alcohol

Heavy drinking during adolescence may leave the adult brain unusually sensitive to alcohol, according to a study published in Molecular Psychiatry. Experiments in male mice found that binge-like drinking during adolescence permanently changed how alcohol affected hippocampal nerve cells, although the altered response was reduced by the medication baclofen.

Adolescence is a period of rapid brain development. Systems involved in seeking rewards become highly active during the teenage years, while brain regions responsible for planning and self-control continue maturing. This imbalance may make adolescents more likely to take risks, including consuming large amounts of alcohol in a short period.

Previous animal studies have linked heavy adolescent drinking with lasting changes in memory, anxiety, impulsivity, and responses to alcohol. However, scientists have known less about the specific cellular processes that could make the developing brain especially vulnerable.

The new study focused on GIRK channels, which are structures in nerve cells that allow potassium to move across the cell membrane. Their activity generally makes nerve cells less likely to fire. Alcohol can activate these channels, helping produce some of alcohol’s effects on the brain. The researchers also examined activin A, a signaling protein involved in brain development, learning, and emotional behavior.

In the study conducted by researchers at Friedrich-Alexander University of Erlangen–Nuremberg, Germany, the team worked with male mice. The animals were either adolescents, approximately 30 to 45 days old, or adults aged three to five months. Adolescent mice were given access to 20% alcohol during their active period for about two weeks. They were then kept alcohol-free until adulthood.

Electrical activity was recorded from nerve cells in the hippocampus, a brain region important for memory and involved in alcohol-related effects. In mice that had never consumed alcohol, activin A had opposite effects depending on age. It increased the cells’ sensitivity to alcohol during adolescence but reduced alcohol sensitivity in adulthood.

This developmental change normally acted like a switch. However, mice that had consumed alcohol heavily during adolescence did not show the usual adult response. Even after a lengthy alcohol-free period, their adult hippocampal cells remained highly sensitive to alcohol.

The altered cells showed stronger GIRK channel activity and became less likely to fire when exposed to alcohol. In some experiments, alcohol suppressed the firing of most tested nerve cells from mice with adolescent drinking experience.

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The team also tested baclofen, a drug that activates GIRK channels and is sometimes prescribed off-label (meaning it is used for a condition it was not officially approved to treat) for alcohol use disorders. In the mouse brain slices, baclofen reduced the unusually large alcohol-induced GIRK response seen after adolescent drinking. The researchers noted: “This finding introduces not only a putative [proposed] new mechanism of therapeutic action, but, with the hippocampus, also a new site of action, with direct implications for [alcohol use disorder]-associated cognitive deficits and affective [mood] disorders.”

The study has several important limitations. For instance, the experiments focused mainly on the hippocampus, while alcohol affects many brain areas. Additionally, the study utilized mice exposed to alcohol for only two weeks, and thus its drinking model may not reflect the variety, duration, or social context of adolescent alcohol use in humans.

The study, “Heavy adolescent drinking makes the adult brain more vulnerable to ethanol by permanently altering the age-dependent interplay between alcohol, GIRK channels and activin,” was authored by Sophia Stürzenberger, Nicolas Bülow, Liubov S. Kalinichenko, Rebecca Licha, Volker Eulenburg, Marc Dahlmanns, Christian P. Müller, Fang Zheng, and Christian Alzheimer.